Viability of ACE-Inhibitors To Reduce Space Radiation-Induced Cardiovascular Injury

Megan Sawant

Thomas Jefferson High School for Science and Technology

This article placed 2nd in the 2023 Teknos Summer Writing Contest.

As I delicately adjusted the temperature sliders in the Lactase Enzyme Lab simulation in my AP Biology class, I impatiently stared at the screen waiting for something to happen. At first, the enzyme lactase seemed to bind to the substrate lactose, causing lactose to split apart into sugar components that could be used in the cell. However, a gentle slide of my fingertip across the mousepad surface, manipulating the temperature, triggered the lactase enzyme to slowly denature and lose its structural form, changing the active site so drastically that lactose could no longer bind to it. This process of changing the active binding site is called inhibition and can be used to correct cell imbalances by negative regulation. In several upcoming studies, angiotensin-converting enzyme inhibitors have been found to reduce the impact of chronic radiation injury.

As astronauts continue to venture into the deep unknowns of space as part of the Artemis missions, the risk of cardiovascular injury from space radiation increases (Dynan et al., 2022). More than 50% of the population exposed to radiation suffer from increased damage to the lungs known as pulmonary toxicity (Sharma et al., 2022). Radiation-induced lung injury first manifests as pneumonitis, characterized by inflammation of the lung tissue and hypertension. Hypertension, known as high blood pressure, occurs when two separate substrates bind to the angiotensin-converting enzyme (ACE) that breaks down the substrates into products that produce a cellular response . The first substrate, angiotensin I, binds to ACE and produces the chemical angiotensin II, causing increased levels of the hormone aldosterone (Moulder et al., 2022). Increased levels of the aldosterone hormone cause the body to retain more sodium, increasing blood pressure. The second substrate, active bradykinin, binds to ACE and is broken down into nonfunctional parts. Bradykinin is originally a vasodilator that expands blood vessels that lower blood pressure; so, bradykinin destruction increases blood pressure. The impact of angiotensin-converting enzymes is immense. Not only do they increase levels of high blood pressure inducing chemicals, but they also destroy regulators to maintain blood pressure.

Several research projects are being conducted on the ACE inhibitor that blocks the ACE enzyme from converting angiotensin I to angiotensin II and breaking down bradykinin (Figure 1). Rittase et al. (2021) demonstrated that ACE-inhibitor captopril was effective in reducing the impacts of radiation exposure in mice. In this study, Göttingen mini pigs were treated with captopril twice a day for 12 days after being exposed to 1.79 joules/kilogram of radiation emitted from the chemical element cobalt. Twenty-one days after radiation exposure, there was a ~33% mortality rate in untreated minipigs compared to a 9% mortality rate in captopril-treated minipigs, showing that the captopril was effective in significantly reducing the mortality rate. Blood cell analysis provided evidence of improved recovery of captopril-treated blood cells. Captopril treatment was also shown to balance cytokines such as CCL2 cytokines and IL5, which are responsible for lowering blood pressure to normal levels. ACE-inhibitors help alleviate radiation-induced cardiovascular injury by reversing hypertension effects and generating cytokines needed to produce healthy bone marrow.

Due to the success of ACE inhibitor captopril, other ACE inhibitors were investigated for treatment. Researchers Sharma et al. (2022) observed the effects of ACE inhibitor lisinopril in rats exposed to a high dose of radiation, similar to the captopril study. Both male and female WAG/RijCmcr rats were treated with 13.4 joules/kilograms of partial body radiation for 70 days. When the rat immune cell compartment was analyzed with computed tomography (CT) scans, rats exposed to lisinopril had reduced accumulation of proinflammatory immune cells and were not subject to lung inflammation (H. Himburg, personal communication, Feb. 17, 2023). Due to the positive results of lisinopril in mitigating radiation effects in rats, scientists investigated the effects of lisinopril in humans. Human monocytes, white blood cells made in the bone marrow, were maintained in an in vitro medium and treated with lisinopril following radiation injury. Lisinopril was found to suppress the development of radiation pneumonitis by blocking the function of ACE inhibitors and the production of angiotensin II.

ACE inhibitors have started to be used for long term treatment to reduce hypertension and major cardiovascular effects. A random sample of 2,939 hypertensive subjects living in Brigella, a rural Italian village, were pulled from the Brisighella Heart Study and split into groups to observe the effects of ACE inhibitors combined with other inhibitors on cardiovascular disease risk. One therapy was the use of statins, which are HMG-CoA reductase inhibitors that block the HMG-CoA enzyme from producing mevalonate, a key component in the cell signaling pathway of generating cholesterol. Inhibition of the HMG-CoA enzyme produces lower cholesterol levels associated with a reduced risk of cardiovascular death. In an 8-year follow-up of the heart study, combined treatment of ACE inhibitors with statins was associated with an 18% reduced risk of the incidence of major cardiovascular problems (Cicero et al., 2022). While the subject population was based in Italy and the sample sizes of the subgroups were relatively small, the study reflects real-world use of the considered anti-hypertensive drugs in subjects.

The promising results of ACE inhibitors in reducing cardiovascular disease caused by space radiation turn scientists to explore the use of inhibition in other medical sectors. A pressing medical issue is the current treatment of severe respiratory syndrome coronavirus 2 (SARS-Cov-2), more commonly known as COVID-19. Scientists Higashi-Kutuwa et al. (2023) have identified TKB-245 and TKB-248 that inhibit the activity of the main protease that significantly blocks the infectivity and replication of various SARS-CoV-2 strains. Incorporation of ACE inhibitors and inhibition processes into therapies to target chronic diseases can help alleviate the COVID-19 pandemic and increase the human ability to send astronauts further into space.

The foundations of enzyme interactions and use of inhibitors/promoters can impact health conditions as miniscule as lactase interaction and as great as cardiovascular disease or COVID-19 diagnosis. The ACE inhibitor blocks the angiotensin converting enzyme that prevents the blood vessels from constricting and producing a high blood pressure in space. Manipulating the concentration of enzymes, the size of the binding substrate, and the shape of the active site significantly change cell signaling pathways and can be used to create treatment plans for other prevalent diseases and pave the way for a healthier future.

References

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[4] Moulder, J. E., Cohen, E. P., Medhora, M., & Fish, B. L. (2022). Angiotensin converting enzyme (ACE) inhibitors as radiation countermeasures for long-duration space flights. Life Sciences in Space Research, 35, 60-68. https://doi.org/10.1016/j.lssr.2022.04.005

[5] Rittase, W. B., Mccart, E. A., Muir, J. M., Bouten, R. M., Slaven, J. E., Mungunsukh, O., Bylicky, M. A., Wilkins, W. L., Lee, S.-H., Gudmundsson, K. O., Di Pucchio, T., Olsen, C. H., Du, Y., & Day, R. M. (2021). Effects of captopril against radiation injuries in the göttingen minipig model of hematopoietic-acute radiation syndrome. Public Library of Science One, 16(8), e0256208. https://doi.org/10.1371/journal.pone.0256208

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